2. Academic Validation
  3. Exploration of imatinib and nilotinib-derived templates as the P2-Ligand for HIV-1 protease inhibitors: Design, synthesis, protein X-ray structural studies, and biological evaluation

Exploration of imatinib and nilotinib-derived templates as the P2-Ligand for HIV-1 protease inhibitors: Design, synthesis, protein X-ray structural studies, and biological evaluation

  • Eur J Med Chem. 2023 Jul 5;255:115385. doi: 10.1016/j.ejmech.2023.115385.
Arun K Ghosh 1,  Jennifer L Mishevich 2,  Satish Kovela 2,  Ryan Shaktah 2,  Ajay K Ghosh 2,  Megan Johnson 2,  Yuan-Fang Wang 3,  Andres Wong-Sam 3,  Johnson Agniswamy 3,  Masayuki Amano 4,  Yuki Takamatsu 5,  Shin-Ichiro Hattori 5,  Irene T Weber 3,  Hiroaki Mitsuya 6
Affiliations

Affiliations

  • 1 Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN, 47907, United States. Electronic address: akghosh@purdue.edu.
  • 2 Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN, 47907, United States.
  • 3 Department of Biology, Georgia State University, Atlanta, GA, 30303, United States.
  • 4 Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Biomedical Sciences, Kumamoto, 860-8556, Japan.
  • 5 Refractory Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, 162-8655, Japan.
  • 6 Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Biomedical Sciences, Kumamoto, 860-8556, Japan; Refractory Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, 162-8655, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States.
PMID: 37150084 DOI: 10.1016/j.ejmech.2023.115385
Abstract

Structure-based design, synthesis, X-ray structural studies, and biological evaluation of a new series of potent HIV-1 Protease Inhibitors are described. These inhibitors contain various pyridyl-pyrimidine, aryl thiazole or alkylthiazole derivatives as the P2 ligands in combination with darunavir-like hydroxyethylamine sulfonamide isosteres. These heterocyclic ligands are inherent to kinase inhibitor drugs, such as nilotinib and imatinib. These ligands are designed to make hydrogen bonding interactions with the backbone atoms in the S2 subsite of HIV-1 Protease. Various benzoic acid derivatives have been synthesized and incorporation of these ligands provided potent inhibitors that exhibited subnanomolar level Protease inhibitory activity and low nanomolar level Antiviral activity. Two high resolution X-ray structures of inhibitor-bound HIV-1 Protease were determined. These structures provided important ligand-binding site interactions for further optimization of this class of Protease Inhibitors.

Keywords

Antiviral; Backbone binding; HIV-1 protease inhibitors; Imatinib; Kinase inhibitors; Nilotinib; Pyridylpyrimidine; X-ray crystal structure.

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